In November 2008, HIV InSite interviewed Jay A. Levy, MD, Professor, Department of Medicine, University of California San Francisco, Research Associate, Cancer Research Institute, and Director, Laboratory for Tumor and AIDS Virus Research.

Heather Dron, MPH, HIV InSite: What were you doing when the epidemic started in the United States (the early 1980s)?

Jay A. Levy, MD: In August 1981, I got a phone from Paul Volberding, who had been a postdoc with me before taking over the oncology program at San Francisco General Hospital. He invited me to come to Grand Rounds because they had a young man with Kaposi sarcoma, and Paul knew I was looking for viruses that cause human cancer. So I went and saw the patient, and began working with Marc Conant to grow Kaposi sarcoma cells in culture, which we succeeded in doing. When we realized that the cause of this syndrome was an immune deficiency, we began to isolate peripheral white cells--there were some problems with updating our biosafety hood and everything--and that led to the discovery of the virus in 1983.

What attracted you to this field (virology)?

"We developed an antibody test...it was an immunofluorescence test...we were testing not only subjects coming to see us, but we began doing it for the kidney transplant service. This was in the early 1980s and we were doing it to screen out people who might be infected..."

Essentially, when I was in college, at the end of the 1950s, I read a paper that talked about viruses that might cause human cancer. The researchers speculated that the virus would hide within the cell but produce proteins and products that transformed the cell. I liked that idea. When I went to medical school, I asked if I could work with some people in the microbiology department who were studying viruses and bacteria that become part of the bacteria and produce substances that are toxins or change the environment within the bacterium. This is a process called lysogeny. I studied that for two years and asked to move into mammalian viruses. In 1964, I went to Uganda and studied Burkitt lymphoma with Denis Burkitt and Tom Bell, who was at the East African Virus Research Institute, and did my first work with mammalian viruses, which got me started.

So it was mainly the viral-cancer link that initially interested you? More specifically, do you want to comment on what attracted you to the field of HIV/AIDS?

We had been working for 10 years at the university on viruses in mice that cause autoimmune disease and cancer. When Paul called me to see the first patient, we just thought it was Kaposi sarcoma in a young man, which is extremely unusual, and he thought it would be a great case for me to isolate a cancer virus, and that got me into AIDS.

And what made you persist in pursuing AIDS research despite the early challenges? What made you catch the bug?

Once I realized how this disease was affecting the San Francisco community, I felt it was my obligation to take on this challenge and find the cause.

What was it like in the beginning of the epidemic for you, and for the community?

It was very difficult in the beginning. Many people didn't know the cause, and some were very frightened. The university was hesitant to have me work in the field, they initially prevented me from moving forward because they were worried about bringing the virus into the university. This delayed our work, but we got by it. At the beginning, all of us faced hesitancy from the university to allow us to work in this field.

For fear of infecting researchers?

There were a variety of reasons, not the least of which is because they didn't want to become an "AIDS university."

Can you list some successes and possible missteps of advocacy and research efforts along the way?

I think the first success really came with our group by finding the virus in 1983. We developed an antibody test, which was very quick. It was an immunofluorescence test, because we wanted a test that could be used all over the world, and there are fluorescent microscopes all over the world. I had done a lot of work in immunofluorescence in virology. The test was quick, specific, and sensitive for what we were doing. We were testing not only subjects coming to see us, but we began doing it for the kidney transplant service. This was in the early 1980s and we were doing it to screen out people who might be infected, then we taught the assay to a variety of groups, including the City Clinic, and they took the immunofluorescence assay and used it in outpatient clinics.

Any missteps or wrong directions?

One was that we were concerned that a retrovirus causing AIDS could not survive the processes that are involved in producing clotting factors for hemophiliacs. But we were in the group, much to my surprise, that showed it did survive. I was concerned that this retrovirus might not be the cause of AIDS in all subjects. That prevented me from reporting the virus in 1983, which may have beaten out the NIH group, who beat us out by 2 months. We were using a mouse virus, which is similar to the AIDS virus. When we announced this finding and asked that the hemophiliac community and the companies pull back their product that hadn't been heated (because we also showed that heat treatment got rid of the virus), they didn't want to do it until we showed that the human virus did it as well. I was too young and too naive to realize that I should have fought back. It took 2 months to do those studies, and in those 2 months, how many hemophiliacs got infected?

Do you have any comment on the major issues facing HIV researchers and policy makers today? What's the most pressing issue?

"No one expected any immune system could fight this virus because it was supposed to kill the immune system, and what we learned is that nature always builds in the exceptions. Now we know that 5-7% of people can survive more than 10 years and have no symptoms...it's due to the immune system."

Prevention and cure. We need to empower women. I thought that Nancy Padian's approach with diaphragms was really pushing for that because biologically it made sense to cover the cervix. But her study was done under the utmost ethical procedures--all the partners were encouraged to use condoms so all she could prove was that diaphragms helped increase the protection from condoms. Microbicides are surprising us all the time. Even the ones that seem rather neutral when they interact with cells--that is, they don't kill cells--don't seem to work, at least in the more recent studies. We need something to protect women, and of course the men too if they have contact through the anal canal. As for cure, we have a big problem. Most companies making drugs target the virus; you can't target the virus-infected cell. The challenge is similar to cancer: If you don't kill every infected cell, it comes back. We are encouraging companies and researchers to look more at the immune system. We are following people who have been infected more than 30 years--long-term survivors--and who are perfectly healthy and have an immune system that works! We've uncovered the mechanism. I'd say that was the second biggest event in our lab. I think we were the first to show that there was a cellular immune response to HIV. No one expected any immune system could fight this virus because it was supposed to kill the immune system, and what we learned is that nature always builds in the exceptions. Now we know that 5-7% of people can survive more than 10 years and have no symptoms and can control the virus, and it is due to the immune system. That is our major area of work now, to show that this one factor that we've identified, not the structure of it but the activity, is produced by these people on a continual basis and it controls the virus.

You work with Dr. Steven Deeks at San Francisco General Hospital with this population?

We share our patients. He is looking at studying long-term survivors, particularly what we call elite controllers, who have no virus in their blood. They aren't as long-lived as our long-term survivors. We have people who have lived 30 years with the virus. Unlike the elites, they have a little virus in their blood. Whether the elites will continue to be that way, I don't know. We do have a few who have gone 10 years with no detectable virus-- extremely unusual ones, probably at the right-hand end of a bell-shaped curve--meaning, if you have a strong immune system response, you will almost completely control the virus, and then there are gradations from there. It shows you that there will always be a population that survives, something that I learned in virology. We've been studying these people since the mid-1980s. What is that now, 20-odd years?

What is the most important lesson you have learned over these past 25 years that HIV researchers and policy makers should keep in mind as we move forward?

"It's taken a long time for people to realize that you have to elicit this natural immunity...which has to be done with a vaccine."

The important lesson is: "An old dog doesn't learn new tricks." Unfortunately, the field is paralyzed by people who come in with an impression from old studies (even young people from reading the literature) and aren't open to a new challenge. This is the first infectious disease we have had to fight by controlling the infected cell in body fluids. Very little attention is given to that. They're always thinking in terms of free virus. Then, you have a virus that exists in many different shades and colors. I think they are very reluctant to take a lesson that we have embraced, which is the natural or innate immune response, which is the earliest response to the virus. We've been emphasizing that from the end of the '90s, when it suddenly hit me that we were looking at innate immunity. It's taken a long time for people to realize that you have to elicit this natural immunity, which we hardly learned about in medical school, which has to be done with a vaccine. Absolutely with a vaccine. That gives time for the immune system to develop a memory to fight this infectious agent. You need, as far I'm concerned, to boost this immunity with treatment, and no company wants to do immune-based therapies. Too complicated.

Do you think that HIV has fundamentally changed the way that we think about and research infectious disease?

Maybe it has now, but it took 25 years. For the majority of researchers, there was a lack of attention to the infected cell, to the innate immunity, to drugs that will help and not harm people, to a microbicide that won't kill the infected cells but prevents them from contact, because if they kill the infected cell they are going to kill vaginal cells. It took them a long time to learn that. I think all the misguided directions have brought people to now say of the vaccine that we've got to fund new research. It's a constant theme.

What are some findings from HIV research that could potentially benefit research into other diseases?

We were the first to show that CD8+ cells can control HIV without killing the infected cell, and now it has been shown for hepatitis viruses, herpes virus. It's now more commonly seen. It may be a major mechanism.

What have you drawn from the experience?

I would have to say it's been meeting an incredible number of infected people. They come to my lab every month and donate blood and are interested and supportive. I dream of the day that we can put all of them in one room--my room here, the lab--and take a picture because we have found what I think is the secret to survival, which is the CD8+ antiviral factor.